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The role of deoxycytidine-metabolizing enzymes in the cytotoxicity induced by 3′-amino-2′,3′-dideoxycytidine and cytosine arabinoside

Mancini, William R.

Mancini, William R.

1992-03

Citation:Mancini, William R.; (1992). "The role of deoxycytidine-metabolizing enzymes in the cytotoxicity induced by 3′-amino-2′,3′-dideoxycytidine and cytosine arabinoside." Cancer Chemotherapy and Pharmacology 30(2): 139-144. <http://hdl.handle.net/2027.42/46922>

Abstract: The cellular metabolism of 3′-amino-2′,3′-dideoxycytidine (3′-NH 2 -dCyd), a cytotoxic agent previously reported to be a poor substrate for purified Cyd/dCyd deaminase (dCydD), was compared with that of cytosine arabinoside (ara-C) in cells that displayed dCydD activity (HeLa) and in cells that did not (L1210). Growth inhibition induced by 3′-NH 2 -dCyd was dependent on the levels of anabolic enzymes, particularly dCyd kinase (dCydK), whereas cytotoxicity induced by ara-C was dependent on the expression of both anabolic and catabolic enzyme activities. Competition kinetics using purified enzyme revealed that the binding affinity of ara-C to dCydK was 5-fold that of the amino analog. However, this binding advantage is apparently offset in cells that contain high levels of dCydD, since the K i values for this enzyme were 0.2 and 23 mm for ara-C and 3′-NH 2 -dCyd, respectively. This was reflected in the decrease in analog sensitivity observed between the two cell lines, whereby the concentrations of ara-C and 3′-NH 2 -dCyd required to inhibit growth by 50% were 200 and 7 times higher, respectively, in the dCydD-containing HeLa cells as compared with the dCydD-deficient L1210 cells. The metabolic stability and cytotoxicity of 3′-NH 2 -dCyd was independent of cell number. An unexpected finding was the extent to which the effectiveness of ara-C could be mitigated by the number of dCydD-containing cells. A completely cytotoxic concentration of ara-C was rendered nontoxic by a 10-fold increase in cell number. This observation was supported by an increase in I-β- d -arabinofuranosyluracil (ara-U) formation, a decrease in ara-C 5′-triphosphate (ara-CTP) accumulation, and a rise in cell viability with increasing cell number. These findings indicate that unlike ara-C, the effectiveness of 3′-NH 2 -dCyd is independent of the level of deaminase, which suggests its possible utility in situations in which high levels of deaminase are manifest.